Hepatitis C virus (HCV) is a positive strand RNA virus in the Flaviviridae family. Its 9.6 kb genome encodes for approximately 10 proteins, including the structural capsid and envelope proteins, as well as the nonstructural proteins NS3 (protease and helicase) and NS5B (polymerase). Ishii et al., Hepatology, 1227 (1999), teaches that the viral RNA-dependent RNA polymerase (RdRp) is responsible both for generating the intermediate minus-strand RNA template and for the synthesis of progeny positive-strand genomic RNA. The authors point out that RdRp is used only in the replication of RNA viruses and has very strict template specificities. The authors conclude that RNA-dependent RNA polymerase enzymes, including HCV RdRp, are ideal targets for antiviral drugs.
HCV is a major human pathogen and is believed to have infected approximately 3% of the worldwide population. Bressanelli et al., Proc. Natl. Acad. Sci. USA, 96: 13034–13039 (1999), teaches that HCV is capable of establishing a persistent infection that can cause chronic hepatitis leading to cirrhosis and hepatocellular carcinoma.
Existing therapies for HCV are limited, and only a few inhibitors of HCV RNA-dependent RNA polymerase are known. There is thus a need to identify additional HCV RdRp inhibitors and to identify the structural features required for potent HCV RdRp inhibitory activity.